This invention relates generally to novel cyclic xcex2-amino acid derivatives as matrix metalloproteases and TNF-xcex1 inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases which are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell-associated cytokine that is processed from a 26kd precursor form to a 17kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-xcex1 converting enzyme (TACE), the enzyme responsible for TNF-xcex1 release from cells, were purified and sequenced (Black et al Nature 1997, 385, 729; Moss et al Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechanisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A: 
wherein Y can be NHOH, R1 and R2 can combine to form a cycloalkyl or heterocyclo alkyl group, R3 and R4 can be a variety of groups including H, and R5 can be substituted aryl.
WO 97/20824 depicts MMP inhibitors of formula B: 
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group.
EP 0,818,442 illustrates MMP inhibitors of formula C: 
wherein Ar is optionally substituted phenyl or naphthyl, z can be absent and X and Y can be a variety of substituents. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TNF-xcex1, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TNF-C, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, one object of the present invention is to provide novel cyclic hydroxamic acids useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds of the present invention for use in therapy.
It is another object of the present invention to provide the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, R2a, R2b, and R3 are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)CoR5, xe2x80x94N(OH)CHO, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94S(O)(xe2x95x90NH)Ra, xe2x80x94SN2H2Ra, xe2x80x94PO (OH)2, and xe2x80x94PO(OH)NHRa;
ring B is a 3-13 membered non-aromatic carbocyclic or heterocyclic ring comprising: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-2 ring heteroatoms selected from O, N, NR2, and S(O)p, provided that ring B contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond;
Z is absent or selected from a C3-13 carbocycle substituted with 0-5 Rb and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRa1, S(O)p, and C(O);
Za is selected from H, a C3-13 carbocycle substituted with 0-5 Rc and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, Cl, F, C1-10 alkylene-Q substituted with 0-3 Rb, C2-10 alkenylene-Q substituted with 0-3 Rb1, C2-10 alkynylene-Q substituted with 0-3 Rb1, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)Oxe2x80x94C2-5 alkenylene, (CRaRa1)r1C(O)Oxe2x80x94C2-5 alkynylene, (CRaRa1)r1OC(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaSO2(CRaRa1)rxe2x80x94Q, and (CRaRa1NRaSO2NRa(CRaRa1)rxe2x80x94Q;
R2a is selected from H, C1-6 alkyl, ORa, NRaRa1, and S(O)pRa;
R2b is H or C1-6 alkyl;
Q is selected from H, a C3-13 carbocycle substituted with 0-5 Rd and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R3 is selected from Q1, Cl, F, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)rC(O)NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)rC(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)rC(O)O(CRaRa1)rxe2x80x94Q1, (CRaRa12)r1S(O)p(CRaRa1)rxe2x80x94Q1, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q1;
Q1 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, and CF2CF3;
Rb1, at each occurrence, is independently selected from ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, and NRaRa1;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I,xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O) NRaRa1, RaNC(O)O, S(O)2NRaRa1NRaS(O)2Ra21NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra, S(O)pRa, CF3, CF2CF3, C3-10 carbocycle substituted with 0-3 Rc1 and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc1;
Rc1, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2S(O)pRa2CF3, and CF2CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O) NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa, CF3, CF2CF3, C3-10 carbocycle and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound of formula II: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-7 membered non-aromatic carbocyclic or heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, and NR2, provided that ring B contains other than a Oxe2x80x94O bond;
Z is absent or selected from a C3-11 carbocycle substituted with 0-4 Rb and a 5-11 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, C(O)NRa1, NRa1C(O)S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C3-10 carbocycle substituted with 0-5 Rc and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)rC(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-5 Rd, and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocycle and a 5-6 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocycle and a 5-6 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula IIIa or IIIb: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
Z is absent or selected from a C5-6 carbocycle substituted with 0-3 Rb and a 5-6 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene
Ya is absent or selected from O and NRa1;
Za is selected from H, a C5-6 carbocycle substituted with 0-3 Rc and a 5-10 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-16 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1C(O)(CRaRa2)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa2)r1C(O)NRaRa1, (CRaRa2)r1C(O)NRa(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-3 Rd and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl, and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
s and s1 combine to total 2, 3, or 4.
[4] In a further preferred embodiment, the present invention provides a novel compound of formula IVa or IVb: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R1 is selected from H, CH3, and CH2CH3;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)rxe2x80x94Q, C(O)O(CRaRa1)rxe2x80x94Q, C(O)NRa(CRaRa1)rxe2x80x94Q, and S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2 at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
r1, at each occurrence, is selected from 0, 1, 2, and 3; and,
s and s1 combine to total 2, 3, or 4.
[5] In another more preferred embodiment, the present invention provides a novel compound of formula II, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
ring B is a 4-7 membered non-aromatic carbocyclic or heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, and NR2, provided that ring B contains other than a Oxe2x80x94O bond;
Z is absent or selected from a C5-6 carbocycle substituted with 0-3 Rb and a 5-6 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-2 alkylene, C2-4 alkenylene, and C2-4 alkynylene
Ya is absent or selected from 0 and NRa1;
Za is selected from H, a C5-6 carbocycle substituted with 0-3 Rc and a 5-10 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is (CRaRa1)r1O(CRaRa1)rxe2x80x94Q or (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-3 Rd and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1 at each occurrence, is selected from 0, 1, 2, 3, and 4.
[6] In another further preferred embodiment, the present invention provides a novel compound of formula II, wherein;
A is xe2x80x94CONHOH;
ring B is a 5-6 membered non-aromatic carbocyclic or heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, and NR2, provided that ring B contains other than a Oxe2x80x94O bond;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R1 is selected from H, CH3, and CH2CH3;
R2 is (CRaRa1)r1O(CRaRa1)rxe2x80x94Q or (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd, and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2 and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2 and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2 CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3; and,
r1, at each occurrence, is selected from 0, 1, 2, and 3.
[7] In another preferred embodiment, the present invention provides a compound selected from the group:
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2xe2x80x2-(trifluoromethyl)[1,1xe2x80x2-biphenyl]-4-carboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[2-(trifluoromethyl)phenoxy]benzamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(3-methyl-2-pyridinyl)benzamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}[1,1xe2x80x2-biphenyl]-4-carboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-phenoxybenzamide
4-(benzyloxy)-N-{(1R, 2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2xe2x80x2-methoxy[1,1xe2x80x2-biphenyl]-4-carboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2xe2x80x2-methyl[1,1xe2x80x2-biphenyl]-4-carboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(2-methoxyphenoxy)benzamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(2-methylphenoxy)benzamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(3-methylphenoxy)benzamide
4-(5,8-dihydro-4-quinolinyl)-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-3xe2x80x2,5xe2x80x2-dimethyl[1,1xe2x80x2-biphenyl]-4-carboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-6-(2-methylphenyl)nicotinamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-6-(2-methoxyphenyl)nicotinamide
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(2,2-dimethylpropanoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(methylsulfonyl)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-methyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
tert-butyl 4-[cis-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)pyrrolidinyl]-1-piperidinecarboxylate
cis-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(4-piperidinyl)-3-pyrrolidinecarboxamide
cis-1-[3-[(1,1-dimethylethoxy)carbonyl]pyrollidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrollidinecarboxamide
cis-N-hydroxy-1-[3-pyrollidinyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrollidinecarboxamide
tert-butyl (3R,4R)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
tert-butyl (3S,4R)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
(3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
tert-butyl (3R,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
(3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(4-pyridinyl)benzamide
(3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide
(3S,4S)-1-allyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-propyl-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-(2-methyl-2-propenyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-isopentyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-neopentyl-3-pyrrolidinecarboxamide
(3S,4S)-1-butyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(3-butenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(2-butynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(2-furylmethyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-[(5-methyl-2-furyl)methyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-3-furancarboxamide
(3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-3-furancarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(1,3-thiazol-2-ylmethyl)-3-pyrrolidinecarboxamide
(3S,4S)-1-acetyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-isobutyryl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-(3-methylbutanoyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(cyclopropylcarbonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(cyclobutylcarbonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-1-(methoxyacetyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-1-(2-furoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-thienylcarbonyl)-3-pyrrolidinecarboxamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-propionyl-3-pyrrolidinecarboxamide
(3R,4S)-4-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-tetrahydro-3-furancarboxamide
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]-4-oxocyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(1R,2S,4R)-4-hydroxy-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(1R,2S,4S)-4-hydroxy-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tetrahydro-2H-pyran-4-yl-3-pyrrolidinecarboxamide
methyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
ethyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
propyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
allyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
isopropyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
2-propynyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
2-butynyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
3-butenyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
benzyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
N-{(1R,2S)-4-(dimethylamino)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
(3S,4S)-4-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide
N-{(1R,2S)-4,4-difluoro-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
(3S,4S)-N-hydroxy-1-isopropyl-4-{[4-(2-methylphenoxy)benzoyl]amino}-3-pyrrolidinecarboxamide
cis-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide
trans-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide
(1S,2R)-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide
(1R,2S)-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide
cis-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclohexanecarboxamide
trans-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclohexanecarboxamide
trans-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide
trans-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide
cis-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide
cis-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide
(3S,4R)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4S)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-[(butoxy)carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-1-[[(1-methylethyl)oxy]carbonyl]-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-1-(methylsulfonyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-3-piperidinecarboxamide
(3S,4R)-1-acetyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-benzoyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-(2,2-dimethylpripionyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-(3,3-dimethylbutanoyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-3-piperidinecarboxamide
(3S,4R)-1-(dimethylcarbamyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-1-methyl-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-ethyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-3-piperidinecarboxamide
(3S,4R)-N-hydroxy-1-(1-methylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-(cyclopropylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-(2,2-dimethylpropyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-benzyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-(2-thiazolylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3R,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-[[(2-methylpropyl)oxy]carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(methoxycarbonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-[(1-methylethoxy)carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(methylsulfonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-4-piperidinecarboxamide
(3S,4S)-1-(3,3-dimethylbutanoyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-benzoyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-[(pyridin-3-yl)carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]aminol-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-thiophenecarbonyl)-4-piperidinecarboxamide
(3S,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[[2-(2-thienyl)ethyl]carbamyl]-4-piperidinecarboxamide
(3S,4S)-1-[(1,1-dimethylethyl)carbamyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-methyl-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-ethyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-cyclobutyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-butyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-methylpropyl)-4-piperidinecarboxamide
(3S,4S)-1-(cyclopropylmethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(2,2-dimethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-cyclopentyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropyranyl)-4-piperidinecarboxamide
(3S,4S)-1-benzyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-thiazolylmethyl)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-pyridinylmethyl)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-pyridinylmethyl)-4-piperidinecarboxamide
(3S,4S) xe2x80x94hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-pyridinylmethyl)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(trans-3-phenyl-2-propenyl)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-phenyl-4-piperidinecarboxamide
(3R,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-methyl-4-piperidinecarboxamide
(3R,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-hexyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(2-fluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(2,2-difluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methylpropyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(1-ethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-[1-[[(1,1-dimethylethyl)oxy]carbonyl]-4-tetrahydropiperidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropiperidinyl)-4-piperidinecarboxamide
(3S,4S)-1-[1-[[(1,1-dimethylethyl)oxy]carbonyl]-3-tetrahydropyrrolidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-tetrahydropyrrolidinyl)-4-piperidinecarboxamide
(3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-thiophenylmethyl)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamide
(3S,4S)-1-[2-(N,N-dimethylamino)-2-oxoethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(benzenesulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(t-butylsulfinyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(2-hydroxylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-[2-[[[(1,1-dimethylethyl)oxy]carbonyl]amino]ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-(2-aminoethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-[2-(N,N-dimethylamino)ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-[(2S)-2-aminopropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-1-[(2R)-2-amino-3-hydroxypropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[[(2R)-2-pyrrolidinyl]methyl]-4-piperidinecarboxamide
(3S,4R)-N-hydroxy-1-(2-hydroxylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-(2-aminoethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3S,4R)-1-cyclobutyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide
(3R,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide
(3S,4S)-1-tert-butyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
tert-butyl 2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoate
2-[(3S 4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoic acid
methyl 2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoate
(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamide
(3S,4S)-1-[2-(dimethylamino)-2-oxoethyl]-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
(3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-4-piperidinecarboxamide
(3S,4S)-1-allyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methyl-2-propynyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-1-(1-methyl-2-propenyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
N-{(1R,2S)-4,5-dihydroxy-2-[(hydroxyamino)carbonyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
(5S)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamide
(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamide
(3S,4S)-3-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-isopropyl-4-piperidinecarboxamide
(3S,4S)-3-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-4-piperidinecarboxamide
tert-butyl (3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
(3S,4S)-N-hydroxy-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide
tert-butyl (3S,4S)-3-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate
(3S,4S)-3-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-N-hydroxy-4-piperidinecarboxamide
(cis, cis)-3-Amino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide
(cis, cis)-3-Methylamino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide
(cis,cis)-3-Dimethylmino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(N-hydroxy)cyclohexylcarboxamide
(cis, trans)-3-Amino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(N-hydroxy)cyclohexylcarboxamide
(cis, trans)-3-Dimethylmino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide
(cis, trans)-3-(1-Methyl-1-ethylmino)-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide
(cis, trans)-3-Methylamino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide
(cis, cis)-3-Hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-{[(2-methyl-4-quinolinyl)methyl]amino}benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-{methyl[(2-methyl-4-quinolinyl)methyl]amino}benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-(3-phenyl-4,5-dihydro-5-isoxazolyl)benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(3-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(2-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-quinolinyl)-4,5-dihydro-5-isoxazolyl]benzamide
4-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5-isoxazolyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide 3-Hydroxy-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzamide
N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[5-(4-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzamide
N-{4-[(hydroxyamino)carbonyl]-3-pyrrolidinyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide
N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide
N-hydroxy-3-({6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthoyl}amino)-4-piperidinecarboxamide
N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthamide
N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-2-naphthamide
N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4-tetrahydro-1-isoquinolinecarboxamide
N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-benzimidazole-5-carboxamide
N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4-carboxamide
(xc2x1)-cis-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1-cycloheptanecarboxamide
(xc2x1)-trans-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1-cycloheptanecarboxamide
(4S,5R)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxohexahydro-1H-azepine-4-carboxamide
(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-4-carboxamide
(3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-3-carboxamide
(4S,5R)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-4-carboxamide
(2S,3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamide
(2R, 3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamide, and
tert-butyl (2S,3R)-2-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating, wherein the disease or condition is referred to as acute infection, acute phase response, age related macular degeneration, alcoholism, anorexia, asthma, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
In another embodiment, the present invention provides novel compounds of the present invention for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc. . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of formula (I) wherein A is hydroxamic acid group are prepared from the corresponding esters via several routes known in the literature (Scheme 1). The methyl ester of 1 (R11xe2x95x90Me) is directly converted to hydroxamic acid 2 by treatment with hydroxylamine under basic conditions such as KOH or NaOMe in solvents such as methanol. The methyl ester of 1 (R11xe2x95x90Me) can also be converted to 0-benzyl protected hydroxamic acid with O--benzylhydroxylamine under similar conditions or using Weinreb""s trimethylalluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp""s bis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods well known in the literature such as hydrogenation using palladium on barium sulfate in hydrogen, to give compound 2. Alternatively, 2 can be prepared through the carboxylic intermediate 3. Carboxylic acid 3 is converted to 2 via coupling with hydroxylamine, or O-benzylhydroxylamine followed by deprotection. 
The xcex2-amino acid moiety in formula (I) can be synthesized following a variety of literature routes as reviewed in xe2x80x9cEnantioselective Synthesis of xcex2-Amino Acidsxe2x80x9d (E. Juaristi, Ed. Wiley-VCH, 1997). One representative approach using Davies protocol is summarized in Scheme 2 (J. Chem. Soc. Perkin Trans I, 1994, 1411). Michael addition of lithium amide 5 to 4 gives cis product 6. The stereochemical configuration of 6 is governed by the chirality of 5. Debenzylation of 6 provides cis-xcex2-amino acid 7. The trans-xcex2-amino acid 9 can be prepared by epimerization of 6 followed by de-benzylation. Since both amine enantiomers of 5 are commercially available, this approach provides ready access to both cis and trans isomers (7 and 9), as well as their antipodes. 
Alternatively, these xcex2-amino acids can be prepared from the corresponding dicarboxylate derivatives (Scheme 3). The dicarboxylate derivatives can be de-symmetrized through enzymatic resolution (for an example with lipase, see Gais, H.-J. et al, J. Am. Chem. Soc. 1989, 54, 5115), or through chemical resolution (for an example with TADOLates, see Seebach, D. et al, Angew Chem Int. Ed. Engl. 1995, 34, 2395). The optically pure mono-ester 11 is converted to Cbz protected xcex2-amino acid ester 12 through Curtius rearrangement (for a related example, see Kobayashi, S. et al, Tetrahedron Lett. 1984, 25, 2557). Removal of Cbz protecting group provides cis amino acid ester 13. The corresponding trans analogue of 13 can be prepared from the ester of trans di-carboxylic acid of 10 following same sequence. 
A series of compounds of formula (I) wherein ring B is pyrrolidine are prepared following the sequence outlined in Scheme 4. Pyrrolidine 15 is prepared following a dipolar addition procedure documented in the literature (Joucla, M.; Mortier, J., J. Chem. Commun. 1985, 1566). Protecting group manipulations and Curtius rearrangement (for a related example, see Kobayashi, S. et al, Tetrahedron Lett. 1984, 25, 2557) give intermediate 17. Hydrogenolysis gives amino acid ester 18. 18 is coupled with acid 20 to provide 21 with R1 as H. To prepare analogues of 21 when R1 is not a hydrogen, 18 is first converted to 19 by alkylation or reductive amination, then coupled with 20. The pyrrolidine nitrogen in 21 is unmasked and functionalized to various tertiary amines, amides, carbamides, ureas, sulfonamides and sulfonyl ureas following procedures well known in the literature. Ester 23 is converted to hydroxamic acid following sequence outlined in Scheme 1. Following the same sequence, the cis isomer of 23 can be prepared using benzyl methyl maleate as the starting material. 
A series of compounds of formula (I) wherein ring B is piperidine are prepared following the sequence outlined in Scheme 5. The xcex2-amino acid moiety is prepared by reduction of enamine 27. Optically pure xcex1-methylbenzylamine (26) is used to induce diastereoselectivity in the reduction (Cimarelli, C. et. al, J. Org. Chem. 1996, 61, 5557). Hydrogenolysis gives amino acid ester 29. 29 is coupled with acid 20 to provide 31 with R1 as H. To prepare analogues of 31 when R1 is not a hydrogen, 29 is first converted to 30 by alkylation or reductive amination, then coupled with 20. The piperidine nitrogen in 31 is unmasked and functionalized to various tertiary amines, amides, carbamides, ureas, sulfonamides and sulfonyl ureas following procedures well known in the literature. Ester 33 is converted to hydroxamic acid following sequence outlined in Scheme 1. Regio-isomers of 33 with piperidine nitrogen transposed to other positions are prepared following a similar sequence. The antipode of 33 can be prepared using the S enantiomer of 26. The transisomer of 33 is prepared by epimerization of 31 or 33 under basic conditions (e.g., DBU, PhMe, at reflux). 
A series of compounds of formula (I) wherein ring B is piperidine and R2a is hydroxy are prepared following the sequence outlined in Scheme 6. Ketone 34 is converted to enol triflate 35 following McMurry triflimide conditions (McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979). Palladium-catalyzed carbonylation in methanol provides methyl ester 36. Epoxidation, epoxide opening with NaN3 and hydrogenation give intermediate 39 with amino and ester groups in cis relationship. The isomer with trans stereochemistry (43) is prepared using Sharpless asymmetric aminohydroxylation and subsequent removal of Cbz group (Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2813). Coupling of 39 and 43 with acid 20 provides 40 and 44, respectively. Esters 40 and 44 are converted to hydroxamic acids following sequence outlined in Scheme 1. 
A series of compounds of formula (I) wherein A is N-formylhydroxylamino group are prepared following the sequence outlined in Scheme 7. Starting from trans-hydroxy ester 45, Wenreib or Roskamp amide formation with O-t-butylhydroxylamine gives 46 (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989 and Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). xcex2-Lactam is formed under Mitsunobu conditions (Mitsunobu, O. Synthesis, 1981, 1). Opening of lactam 47 with methylamine followed by N-formylation provide 49. The N-methyl amide moiety of 49 is converted to carboxylic acid by nitrosation with N204 or NaNO2, and hydrolysis with LiOOH (Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38, 4535). Acid 50 is converted to 53 as described previously. Acid hydrolysis of t-Butyl group in 53 completes the synthesis. 
A series of compounds of formula (I) wherein A is mercaptomethyl group are prepared following the sequence outlined in Scheme 8. Saponification and hydroboration of 55 give alcohol 57. Mitsunobu reaction with thioacetic acid followed by lithium hydroxide hydrolysis provides the desired thiol 59. 
A variety of compounds of formula (I) wherein Z-Ua-Xa-Ya-Za is a functionalized phenyl group can be prepared by methods described in Scheme 9. Intermediate 60, available from schemes described previously, is converted to phenol 61 by hydrogenolysis. Phenol 61 is used as common intermediates for structure diversification. Reaction of 61 with R10xe2x80x94X provides 62, an alternative is the reaction of 61 with R10xe2x80x94OH under Mitsunobu conditions to produce 62. R10 can be appended directly to the aromatic ring by converting 61 to an aryl triflate then reaction with an organometallic in the presence of a palladium (0) catalyst to give 63. 61 can also be reacted with acyl halides or isocyanates to afford 66. Biaryl ethers 65 can be produced by treatment of 61 with aryl boronic acids in the presence of a copper catalyst. Esters 62-63 and 65-66 are converted to the hydroxamic acids following the sequences outlined in Scheme 1. 
Compounds of formula 76 can be prepared starting from the commercially available 3-hydroxy-2-nitrobenzoic acid 67 (Scheme 10). Conversion of the carboxylic acid to an ester such as an ethyl ester 68 can be accomplished by refluxing in EtOH/benzene in the presence of sulfuric acid. Ester 68 can be reduced to a saturated cyclohexyl ring 69 by hydrogenation in acidic aqueous solution using a catalyst such as PtO2. Coupling of 69 with a benzoic acid derivative 70 using a coupling agent such as BOP produces the amide derivative 71 as the major diastereomer with a cis, cis-stereochemistry. The hydroxyl group of 71 can be oxidized using an oxidizing agent such as the Dess-Martin periodinane to give a ketone derivative 72. Reductive amination of 72 with ammonium acetate or a primary amine using a reducing agent such as Na(OAc)3BH affords the amino derivative 73. After Boc protection at the amino using di-tert-butyl-dicarbonate, saponification of the ethyl ester 74 at an elevated temperature using a base such as KOH in MeOH/H2O followed by coupling of the resulting carboxylic acid with hydroxylamine hydrochloride using a coupling agent such as BOP produces the hydroxamic acid 75. Removal of the Boc group using an acid such TFA/CH2Cl2 or 4 N HCl in dioxane affords the final compounds of formula 76.
Compounds of formula 78 can be obtained by reductive amination of the intermediate 73 with an aldehyde using a reducing agent such as Na(OAc)3BH followed by conversion of the ethyl ester to a hydroxamate as shown in Scheme 11. 
Compounds of formula 80 can be obtained by reductive amination of the intermediate 72 with a cycloamine such as azetidine, pyrrolidine, piperidine or morpholine using a reducing agent such as Na(OAc)3BH followed by conversion of the ethyl ester to a hydroxamate as shown in Scheme 12. 
Compound of formula 89 can be synthesized starting from the intermediate 69 which is coupled with 4-benzyloxybenzoic acid 81 using a coupling agent such as BOP, producing 82 as the major diastereomer with a cis, cis-stereochemistry (Scheme 13). The hydroxyl group can be converted to a sulfonate such as a mesylate 83. Displacement of 83 with sodium azide produces the azido derivative 84 which is subjected to a hydrogenolysis using a catalyst such as Pdxe2x80x94C to give the primary amine 85. Mono Boc protection at the amino group is accomplished by reaction of 85 with di-tert-butyl-dicarbonate in THF/H20 using a mixed base such as NaOH/NaHCO3. Alkylation of 86 with 4-chloromethyl-2-methylquinoline using a base such as potassium carbonate in acetone at reflux affords the intermediate 87. Following saponification using a base such as KOH in MeOH/H2O at an elevated temperature, the resulting carboxylic acid 88 is coupled with hydroxylamine hydrochloride using a coupling agent such as BOP. Removal of the Boc group using an acid such as TFA/CH2Cl2 produces the final compound 89. 
Compounds of formula 92 can be prepared starting from the intermediate 87 (Scheme 14). Saponification using a base such as KOH in MeOH at an elevated temperature followed by deprotection of the Boc group using an acid such as TFA in CH2Cl2 produces the amino-carboxylic acid intermediate 90. Reductive amination of 90 with a ketone using a reducing agent such as Na(OAc)3BH produces the secondary amine 91. The hydroxamic acids of formula 92 can be obtained by coupling the carboxylic acid with hydroxylamine hydrochloride using a coupling agent such as BOP. 
Compounds of formula 95 can be obtained by reductive amination of the intermediate 90 with an aldehyde using a reducing agent such as Na(OAc)3BH followed by conversion of the carboxylic acid to a hydroxamic acid as shown in Scheme 15. 
Compounds of formula 103 can be prepared starting from the intermediate 85 (Scheme 16). The mono-benzylated amino derivative 97 can be obtained by reductive amination of the intermediate 85 with excess benzaldehyde using a reducing agent such as Na(OAc)3BH followed by hydrogenation under atmospheric pressure using a catalyst such as Pdxe2x80x94C. Further alkylation at the benzylamino group by reductive amination with an aldehyde using a reducing agent such as Na(OAc)3BH produces the tertiary amino derivative 98. After removal of the benzyl group by hydrogenation, the secondary amine is protected by reaction with di-tert-butyl-dicarbonate. Alkylation of the phenol derivative 100 with 4-chloromethyl-2-methylquinoline is followed by saponification of the ethyl ester using a base such as KOH in MeOH at reflux. Conversion of the carboxylic acid to a hydroxamic acid followed by acid deprotection of the Boc group affords compounds of formula 103.
Compounds of formula 108 can be prepared starting from the intermediate 83 (Scheme 17). Displacement of 83 with ArOH produces the aryl ether 104. After removal of the benzyl group by hydrogenation using a catalyst such as Pdxe2x80x94C, the phenol moiety is alkylated with 4-chloromethyl-2-methylquinoline. Saponification of the ethyl ester using a base such as KOH in MeOH at reflux followed by coupling of the resulting carboxylic acid with hydroxylamine hydrochloride using a coupling agent such as BOP affords compounds of formula 108. 
The 3-hydroxyl analog of formula 110 can be prepared starting from the intermediate 71. Saponification using a base such as LiOH followed by coupling the resulting carboxylic acid with hydroxylamine hydrochloride using a coupling agent such as BOP provides the the final product with a cis, cis-stereochemistry. 
The cis-trans-diastereomeric analog of 110 can be prepared starting from the same intermediate 71. Inversion of the chirality at the 3-hydroxyl position can be accomplished by a Mitsunobu reaction with 4-nitrobenzoic acid. Hydrolysis using a base such as KOH removes the 4-nitrobenzoyl moiety and saponifies the ethyl ester. Coupling of the resulting carboxylic acid with hydroxylamine hydrochloride using a coupling agent such as BOP provides compound of formula 112. 
A series of compound of formula (I) where ring B is tetrahydropyran are prepared following the sequence outlined in Scheme 20. Treatment of the enolate of tetrahydropyranone 113 with Mander""s reagent provides xcex2-keto ester 114. Condensation of 114 with amine 115 gives enamine 116. Reduction of 116 with sodium (triacetoxy)borohydride proceeds stereoselectively to give desired amine 117. Hydrogenolysis and coupling with acid 20 provides ester 119. Ester 119 is converted to hydroxamic acid following sequence outline in Scheme 1.
Compounds of formula (I) wherein ring B is a tetrahydrofuran are prepared as outlined in Schemes 21 and 22. Michael addition of the sodium salt of methyl glycolate 120 to methyl acrylate and concomitant Dieckman cyclization provides the keto-ester 121. Enamine formation with (R)-xcex1-methylbenzyl amine 115 and diastereoselective reduction gives 123. Hydrogenolysis gives the amino acid ester 124. 124 is coupled to acid 20 and converted to the hydroxamate 126. 
An alternative preparation (Scheme 22) of the amino acid ester 124 begins with the intermediate 121. Enamine formation with NH4OAc and acetylation gives 128. Asymmetric hydrogenation using a chiral rhodium catalyst (J. Am. Chem. Soc. 1995, 117, 9375) and de-acetylation would yield 124 that could be converted similarly to hydroxamate 126.
Another procedure for the synthesis of cyclic xcex2-amino acids useful for the preparation of compounds of formula I uses the well documented [2+2] cycloaddition of chlorosulfonylisocyanate with olefins (Scheme 23, Dhar, D. N.; Murthy, K. S. K. Synthesis 1986, 437-449). When 130 is reacted with chlorosulfonylisocyanate the resulting xcex2-lactam intermediate 131 can be opened to afford cyclic xcex2-amino acids using a variety of conditions, but most conveniently with chlorotrimethylsilane/methanol. The methyl ester 13 can then be converted to compounds of formula I followed our usual procedure of attaching carboxcylic acid 20 to provide 132 then hydroxamic acid 133 is formed by our standard conditions. The trans xcex2-amino acids 134 are available by equilibration of cis amide ester 132 under basic conditions. 
An alternative synthesis of 133 begins with formation of benzyl hydroxamate 136 from trans xcex2-hydroxy carboxylate 135 (Scheme 24). Intramolecular cyclization of 136 under Mitsunobu conditions (Bellettini, J. R.; Miller, M. J. Tetrahedron Letters 1997, 38, 167-168) then affords benzyl protected hydroxy xcex2-lactam 137. Removal of the benzyl group by hydrogenolysis and reduction of the intermediate N-hydroxy xcex2-lactam provides 131, which can be converted to final products as shown in the previous scheme. 
A synthesis of cyclic lactam xcex2-amino acids begins conveniently with ketone 138 (Scheme 25). Oxime 139 is formed with hydroxylamine hydrochloride, sodium bicarbonate in refluxing methanol and is then treated with p-toluenesulfonyl chloride to give Beckmann rearrangement precursor 140. The rearrangement can be driven by a variety of conditions with silica gel/chloroform providing a straightforward mild procedure to form lactam 141. Conversion of 141 to hydroxamate 142 uses conditions outline in previous schemes. 
Compounds of formula 147 can be prepared using the protocol described in Scheme 26. Alkylation of methyl 4-aminobenzoate or methyl 4-methylaminobenzoate 143 with 4-chloromethyl-2-methylquinoline using K2CO3 in DMF at 100xc2x0 C. produced the secondary or tertiary amine 144. Following saponification, the resulting carboxylic acid 145 was coupled with a cyclic xcex2-aminoacid derivative using a coupling agent such as BOP to give the amide 146. Conversion of the ester in 146 to a hydroxamic acid using hydroxylamine afforded the final product 147.
Compounds of formula 154 can be prepared according to Scheme 27. An aldehyde 148 was treated with hydroxylamine to provide an oxime 149. Cycloaddition of 149 with an olefin 150 using bleach produced the isoxazoline derivative 151. Hydrolysis of the ester followed by coupling with a cyclic xcex2-aminoacid derivative afforded the amide 153. Treatment of 153 with a hydroxylamine solution produced the hydroxamic acid 154.
Compounds of formula 161 can be prepared using the sequence as illustrated in Scheme 28. An aldehyde 155 was treated with hydroxylamine to give an oxime 156. Cycloaddition of 146 with an olefin 157 using bleach produced the isoxazoline derivative 158. Following saponification, the resulting carboxylic acid 159 was condensed with a cyclic xcex2-aminoacid to give the amide 160. Treatment of 160 with a hydroxylamine solution afforded the hydroxamic acid 161.
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tetr. Lett. 1995, 36, 8937-8940.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.